Proinflammatory P2Y14 receptor inhibition protects against ischemic acute kidney injury in mice
Maria Agustina Battistone, … , Dennis Brown, Sylvie Breton
Maria Agustina Battistone, … , Dennis Brown, Sylvie Breton
Published April 14, 2020
Citation Information: J Clin Invest. 2020;130(7):3734-3749. https://doi.org/10.1172/JCI134791.
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Research Article Inflammation Nephrology

Proinflammatory P2Y14 receptor inhibition protects against ischemic acute kidney injury in mice

Abstract

Ischemic acute kidney injury (AKI), a complication that frequently occurs in hospital settings, is often associated with hemodynamic compromise, sepsis, cardiac surgery, or exposure to nephrotoxins. Here, using a murine renal ischemia/reperfusion injury (IRI) model, we show that intercalated cells (ICs) rapidly adopted a proinflammatory phenotype after IRI. Wwe demonstrate that during the early phase of AKI either blockade of the proinflammatory P2Y14 receptor located on the apical membrane of ICs or ablation of the gene encoding the P2Y14 receptor in ICs (a) inhibited IRI-induced increase of chemokine expression in ICs, (b) reduced neutrophil and monocyte renal infiltration, (c) reduced the extent of kidney dysfunction, and (d) attenuated proximal tubule damage. These observations indicate that the P2Y14 receptor participates in the very first inflammatory steps associated with ischemic AKI. In addition, we show that the concentration of the P2Y14 receptor ligand UDP-glucose (UDP-Glc) was higher in urine samples from intensive care unit patients who developed AKI compared with patients without AKI. In particular, we observed a strong correlation between UDP-Glc concentration and the development of AKI in cardiac surgery patients. Our study identifies the UDP-Glc/P2Y14 receptor axis as a potential target for the prevention and/or attenuation of ischemic AKI.

Authors

Maria Agustina Battistone, Alexandra C. Mendelsohn, Raul German Spallanzani, Andrew S. Allegretti, Rachel N. Liberman, Juliana Sesma, Sahir Kalim, Susan M. Wall, Joseph V. Bonventre, Eduardo R. Lazarowski, Dennis Brown, Sylvie Breton

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Figure 10

Elevated UDP-Glc urinary levels are associated with AKI in ICU and cardiac surgery patients.

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Elevated UDP-Glc urinary levels are associated with AKI in ICU and cardi...
(A) Average peak urinary UDP-Glc concentration in ICU patients with AKI (ICU-AKI, n = 12) and without AKI (No AKI, n = 23). Significantly higher UDP-Glc concentration was detected in patients who developed AKI versus patients who did not. (B) Average peak urinary UDP-Glc concentration in cardiac surgery patients with AKI (CS-AKI, n = 6) and without AKI (No AKI, n = 20). Significantly higher UDP-Glc concentration was detected in patients who developed AKI versus patients who did not. (C) Receiver operating characteristic (ROC) curve for the diagnosis of AKI (stages 1, 2, and 3 combined) in ICU patients. Peak UDP-Glc levels versus the higher AKI stage for each patient were compared. (D) ROC curve for the diagnosis of AKI (stages 1, 2, and 3 combined) in cardiac surgery patients. Data are expressed as median ± IQR for continuous variables from a cohort of 35 patients. (A and B) Statistical analysis was performed using Wilcoxon’s rank-sum test, χ2 test, and Fisher exact test. (C and D) A χ2 test was performed to compare the area under the ROC curve (AUC) with that of an intercept-only model, which has an AUC of 0.5. Two-sided P values less than 0.05 were considered statistically significant.